Phosphorylation of ACTN4 and Podocyte Vulnerability in Diabetic Kidney Disease
Abstract
This 2-year project will investigate essential cells of the kidney called podocytes as potential targets for future treatments of diabetic kidney disease. This project addresses the FY20 PRMRP topic areas of research studying diabetes and its complications as well as focal segmental glomerulosclerosis (a type of kidney disease that can result from diabetes). Although podocytes play an important role in the development of diabetic kidney disease, there have yet to be therapies that directly target podocytes to protect them while they face the mechanical forces of filtering blood within the kidney. Previous research has shown that when the podocyte cytoskeleton—the structural scaffold of the cell—contains defects, the podocyte becomes vulnerable to mechanical forces and detaches from its foundation within the kidney. This detachment leads to progressive kidney damage. More recently, it was found that a biochemical pathway triggered by high glucose alters the podocyte cytoskeleton to render it more vulnerable to these mechanical forces. Whereas previous research involving defects in the podocyte cytoskeleton has centered on genetic mutations, the research proposed here will determine whether this newly discovered biochemical pathway is active in diabetic kidney disease and whether it can be targeted for future treatments. First, this pathway will be studied in human samples including kidney tissue from the National Disease Research Interchange. A sensitive technique will be applied to this tissue to measure whether this pathway is more active in tissue from diabetic patients with kidney disease versus healthy patients. Next, rigorous controlled experiments using diabetic mouse models will be used to determine whether inhibiting this biochemical pathway reduces the severity of kidney injury. Finally, experiments will identify the protein(s) that is stimulated by glucose and in turn catalyzes the biochemical pathway that renders the podocyte vulnerable to mechanical forces in the kidney. Inhibition of this protein(s) will be studied in future research as novel treatment strategy in diabetic kidney disease. The research proposed in this application applies innovative approaches and the latest bioengineering technology to accomplish the studies described above. Completion of the proposed studies will open up a new paradigm for future treatments of diabetic kidney disease. The impact of this work will be wide-ranging across civilians as well as active and retired military personnel who are affected by diabetic kidney disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110054
Entities
People
- Di Feng
Organizations
- Beth Israel Deaconess Medical Center
- United States Army